As we age, our lenses undergo physiological changes that make it more difficult to focus on near objects. That is why nearly everyone requires reading glasses, even as early as age 35-40. The ability of the eye to change focal power, also known as accommodative amplitude, decreases significantly with age. The accommodative amplitude is 20 diopters in children and young adults, but it decreases to 10 diopters by age 25 and to ≦1 diopter by age 60. The age-related inability to focus on near objects is called presbyopia. All of us will develop presbyopia and will require corrective lenses unless a new treatment is found.
In a healthy eye, the ciliary muscle can deform the lens via the suspensory ligaments to change the focal power of the eye. The lens takes on a different shape when the ciliary muscle is relaxed for near vision (FIG. 2A) than when the ciliary muscle is contracted for far vision (FIG. 2B). When the ciliary muscle is relaxed, the central thickness is larger, and the equatorial circumference is smaller. Also, the lens nucleus is more posterior than central, and the space between iris and lens is larger. These changes involve the fibers of the lens cortex (C) because even by young adulthood, the lens nucleus (N) is incompressible.
The ciliary muscle, the suspensory ligaments, the posterior chamber of the aqueous humor, and the lens all must be considered when defining the etiology of presbyopia. Presbyopia may be caused, in part, by lens growth, oxidative stress, and disulfide bond formation.
The lens is a unique stratified epithelium where new fiber cells are laid down in shells throughout life. But the older fibers are not sloughed, so cross-sectional area, equatorial circumference, total volume, and weight increase all with age. The anterior part of each fiber cell must differ from that of the posterior because the anterior cortex is thicker than the posterior. Furthermore, elasticity decreases in the anterior cortex with age. Because of the change in lens size, the amount of force required to change its shape increases. The circumlental space decreases causing the posterior aqueous volume to decrease. This phenomenon is more pronounced in the temporal quadrant. There are also aging changes in the ciliary muscle and suspensory ligaments that contribute to the loss of lens deformability.
Although growth is a major contributor to the decreased deformability in the presbyopic lens, small changes in fiber membrane and/or cytoskeleton structure also play a role. Lens fiber plasma membranes are relatively stable and immobile due to the high levels of sphingomyelin and cholesterol that ranges from 50 percent in the cortex to 90 percent in the nucleus. While targeting lens membrane lipids may improve deformability, it may increase the risk for cataract because cataract is associated with decreased cholesterol.
The cytoskeleton is equally critical for fiber stability and elasticity. The lens fiber has actin microfilaments, a unique beaded intermediate filament, and microtubules, all of which are associated with the inner leaflet of the fiber plasma membrane. Disulfide bonds in intrinsic membranes and in membrane associated proteins increase with age in the non-cataractous human lens and in rodent lenses. Glutathione, believed to be the lens' major defense against oxidation, decreases with age and with distance from the lens surface. In other systems, glutathionylation of actin causes actin-microfilament depolymerization. Actin microfilaments are the most elastic of the cytoskeletal components.
Such disulfide bonds can also induce cataract. Oxidative stress can oxidize lens proteins, which destroys the balanced redox state required to maintain transparency. Thiolation of lens protein changes the tertiary structure of the protein, and more functional groups are exposed for further modification. The first line of defense, endogenously high levels of glutathione, fends off reactive oxygen species and keep lens proteins in a reduced state. As a second line of defense, intrinsic repair enzymes dethiolate the protein-thiol mixed disulfides or protein-protein disulfides induced by oxidative stress, thus keeping lens proteins thiols free and restoring lens proteins-enzyme function and activity.
With age, these protection and repair mechanisms against oxidative stress slowly deteriorate and become ineffective, resulting in a lens less able to counteract the effects of reactive oxygen species and other oxidants. Sulfhydrals are among groups most susceptible to oxidation. Sulfhydral groups may then undergo oxidation creating intra- and inter-molecular cross-links which increases with age in normal human lenses. These disulfide cross-links are present in water insoluble protein fractions. High molecular weight aggregates containing proteins and membrane particles with sizes over 5×107 Da will scatter light. When a sufficient number of high molecular weight protein aggregates of this size or greater occur, transparency is lost and cataract occurs. Thus disulfide bond formation may be a cause of both presbyopia and cataract.
Both presbyopia and cataract are age-related and may share common etiologies such as lens growth, oxidative stress, and/or disulfide bond formation.
There is a need for agents, compounds, compositions, and methods for combating ocular disease, including presbyopia and/or cataract. The agents, compounds, compositions, and methods described herein can be prophylactic and/or therapeutic for presbyopia and cataract by preventing or reducing disulfide bond formation in lens membranes and membrane associated proteins. The agents, compounds, compositions, and methods may also affect one or more of lens growth, lens cystine and lipoic acid concentrations, cellular and lens fiber redox state, cellular elasticity, and lens transparency.